The present invention relates to novel urea derivatives which have TNF-xcex1 production inhibitory effects and are useful as therapeutic agents for various diseases, particularly as therapeutic agents for autoimmune diseases such as rheumatoid arthritis, and to novel compounds which are useful as synthetic intermediates thereof.
TNF-xcex1 (tumor necrosis factor-xcex1) was found as a factor which induces hemorrhagic necrosis at tumor sites, and it is now recognized as a cytokine which widely participates in biophylaxis-immune mechanism through inflammation. However, prolonged and excessive production of TNF-xcex1 causes tissue disorders and is a factor which brings about causes and exacerbation of various diseases. Accordingly, it is reported that it is important to suppress the excessive production of TNF-xcex1 in morbidity where TNF-xcex1 is excessively produced (Yamazaki, Clinical Immunology, 27, 1270, 1995). The above-mentioned literature recites many pathema such as arthrorheumatism, systemic lupus erythematosus (SLE), cachexia, acute infectious disease, allergy, pyrexia, anemia and diabetes as examples of pathema in which TNF-xcex1 participates.
It is reported that TNF-xcex1 plays an important role in crises of rheumatoid arthritis and Crohn""s disease; which are autoimmune diseases (Andreas Eigler et al., Immunology Today, 18, 487, 1997).
TNF-xcex1 is known to participate in various diseases as well as autoimmune diseases such as rheumatoid arthritis, Crohn""s disease and systemic lupus erythematosus as reported in the above-mentioned literatures and the like. Compounds which inhibit its production or suppress its effect are expected to be useful for treatment of various diseases, and many studies have been done. Outlines of these studies of drugs are introduced in the above-mentioned literatures (Yamazaki, Clinical Immunology, 27, 1270, 1995, Andreas Eigler et al., Immunology Today, 18, 487, 1997). Recently, it was found that a proteolytic enzyme participating in secretion of TNF-xcex1 is metalloprotease, and a study of TNF-xcex1 production inhibitory effects of metalloprotease inhibitors is also reported (Published Japanese Translation of PCT No. 508115/1997).
Various drugs having the TNF-xcex1 production inhibitory effects have been studied as mentioned above. Focusing attention on chemical structure of the drugs, however, no drug having a chemical structural feature of compounds of the present invention is known at all. The chemical structural feature of the compounds of the present invention is that the compounds have urea structure as basic structure and have a sulfur atom and an amide bond in side chains. Few studies of such drugs having the urea structure as basic skeleton have been reported. Moreover, no drug having a sulfur atom in a side chain has hitherto practically been reported.
Since the compounds having the urea structure as the basic structure and having a sulfur atom and the amide bond in the side chains have not practically been reported as mentioned above, a study of synthesis of such compounds and a study of pharmacological actions, particularly the TNF-xcex1 production inhibitory effects of the compounds were very interesting subjects.
The present inventors focused attention on urea structure of which application to drugs had hardly been studied, made studies on synthesis of novel urea derivatives wherein sulfur is introduced into one side chain thereof and an amide bond is introduced into the other side chain thereof, and succeeded in preparing many novel compounds. The present inventors further studied pharmacological actions of the compounds and found that these novel compounds have excellent TNF-xcex1 production inhibitory effects. In a process of the study on preparing the above-mentioned novel urea derivatives, the present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates of the derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as xe2x80x9cthe present compoundxe2x80x9d as far as there is no proviso), medicinal compositions containing it as an active ingredient, and compounds which are represented by the general formula [III] and are useful as synthetic intermediates of the present compounds and salts thereof (hereinafter referred to as xe2x80x9cthe present synthetic intermediatexe2x80x9d as far as there is no proviso). 
wherein
R1 is hydrogen, lower alkyl, an aromatic group, RAxe2x80x94COxe2x80x94, RCxe2x80x94Sxe2x80x94 or a group of the following formula [II]: 
R2, R3 and R4, being the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl or an aromatic group. When R4 is lower alkyl, terminal carbon of the lower alkyl can join with carbon to which the alkyl is bonded to form a cycloalkyl ring.
R5 and R6, being the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl or an aromatic group. When both R5 and R6 are lower alkyl, they can join each other to form a nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring, and the heterocyclic ring can be substituted by lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, an aromatic group or RAxe2x80x94COxe2x80x94.
R7 is hydrogen, lower alkyl, cycloalkyl, hydroxy, mercapto, phenyl, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 or xe2x80x94CONHOH. R7 can join with sulfur adjacent to A1 to form a nonaromatic heterocyclic ring containing sulfur in the ring, and the ring can further have carbonyl in the ring.
A1 is lower alkylene.
A2 is lower alkylene.
Each lower alkyl defined above can be substituted by hydroxy, a nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring, cycloalkyl, cycloalkenyl, adamantyl, an aromatic group, phthalimido, guanidino which can be substituted by lower alkylsulfonyl or aromatic sulfonyl, RAxe2x80x94COxe2x80x94, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94, RHxe2x80x94N(RJ)COxe2x80x94, RKxe2x80x94CONHxe2x80x94 or xe2x80x94CONHOH.
Each lower alkenyl defined above can be substituted by hydroxy, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl or an aromatic group.
Each cycloalkyl defined above can be substituted by lower alkyl, hydroxy, oxo or RExe2x80x94OCOxe2x80x94.
Each aromatic group defined above can be substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, an aromatic group, lower alkylsulfonyl, aromatic sulfonyl, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 or RKxe2x80x94CONHxe2x80x94.
The nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring defined above can be substituted by lower alkyl, cycloalkyl, an aromatic group or RAxe2x80x94COxe2x80x94, and the lower alkyl can be substituted by hydroxy, cycloalkyl, cycloalkenyl, an aromatic group, RAxe2x80x94COxe2x80x94, RBxe2x80x94Oxe2x80x94, RExe2x80x94OCOxe2x80x94 or RFxe2x80x94N(RG)xe2x80x94.
RA is lower alkyl, halogeno-lower alkyl, an aromatic group, lower alkoxy, aromatic-lower alkoxy or RFxe2x80x94N(RG)xe2x80x94. RB is lower alkyl or an aromatic group. RC is hydrogen, lower alkyl or an aromatic group. RD is lower alkyl or an aromatic group. RE is hydrogen, lower alkyl or an aromatic group. RF and RG, being the same or different, are hydrogen, lower alkyl, cycloalkyl or an aromatic group. RH and RJ, being the same or different, are hydrogen, lower alkyl, cycloalkyl or an aromatic group. RK is lower alkyl, lower alkoxy or an aromatic group. The same definitions are applied hereinafter.]
[The same definitions are applied except for a case where R7 joins with adjacent sulfur to form a nonaromatic heterocyclic ring containing sulfur in the ring. Hereinafter, a definition of R7 to be used for the synthetic intermediates is the same as that mentioned above.]
The groups defined above are hereinafter described in detail.
The lower alkyl is straight-chain or branched alkyl having one to eight carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, t-butyl or 3,3-dimethylbutyl.
The lower alkenyl is straight-chain or branched alkenyl having two to eight carbon atoms such as vinyl, allyl, 3-butenyl, 5-hexenyl or isopropenyl.
The cycloalkyl is cycloalkyl having three to eight carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The cycloalkenyl is cycloalkenyl having three to eight carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
The lower alkoxy is straight-chain or branched alkoxy having one to eight carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or t-butoxy.
The halogen is fluorine, chlorine, bromine or iodine.
The lower alkylene is straight-chain or branched alkylene having one to eight carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, ethylethylene, dimethylethylene, propylethylene, isopropylethylene or methyltrimethylene.
The aromatic group is a monocyclic or condensed polycyclic hydrocarbon aromatic group such as phenyl or naphthyl, or a heterocyclic aromatic group such as pyridyl, thienyl or imidazolyl.
The nonaromatic heterocyclic ring having nitrogen and/or oxygen in the ring is a nonaromatic heterocyclic ring having one or two nitrogen atoms in the ring such as piperidine, piperazine, pyrroline or homopiperazine, or a nonaromatic heterocyclic ring having nitrogen and oxygen in the ring such as morpholine.
The nonaromatic heterocyclic ring containing sulfur in the ring is a nonaromatic heterocyclic ring containing one or two sulfur atoms in the ring such as dithiolane, or a nonaromatic heterocyclic ring further having ketone in the ring such as thiolactone.
Salts in the present invention refer to any pharmaceutically acceptable salts, and examples thereof are salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid, citric acid, tartaric acid, diacyltartaric acid, benzoic acid or a substituted benzoic acid, salts with an alkali metal or an alkaline-earth metal such as sodium, potassium or calcium, and the like. When geometrical isomers or optical isomers are present in the present compounds or the present intermediates, these isomers are also included in the scope of the present invention. The present compounds or the present intermediates can be in the form of addition salts such as hydrates and organic solvates.
Preferred examples of the present compound are the following.
Compounds and salts thereof wherein the group(s) in the general formula [I] is defined by anyone selected from the following 1) to 8) or any combinations consisting of 1) to 8).
1) R1 is selected from hydrogen, lower alkyl, phenyl, RAxe2x80x94COxe2x80x94, RCxe2x80x94Sxe2x80x94 and a group of the following formula [II]; 
RA is selected from lower alkyl, lower alkoxy, phenyl, pyridyl, phenyl-lower alkoxy and RFxe2x80x94N(RG)xe2x80x94, RC is selected from lower alkyl and phenyl, RF and RG, being the same or different, are selected from hydrogen, lower alkyl and phenyl, each lower alkyl can be substituted by phenyl or lower alkoxycarbonyl, and each phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, halogen and nitro;
2) R2, R3 and R4, being the same or different, are selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, phenyl and naphthyl, the lower alkyl can be substituted by a group selected from hydroxy, cycloalkyl, cycloalkenyl, adamantyl, phenyl, naphthyl, pyridyl, thienyl, imidazolyl, guanidino which can be substituted by lower alkylsulfonyl or phenylsulfonyl, xe2x80x94RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, REOCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 and RKxe2x80x94CONHxe2x80x94, the lower alkenyl can be substituted by lower alkyl, phenyl or naphthyl, RB is selected from lower alkyl and phenyl, RC is selected from hydrogen, lower alkyl and phenyl, RD is selected from lower alkyl and phenyl, RE is selected from hydrogen, lower alkyl and phenyl, RF and RG, being the same or different, are selected from hydrogen, lower alkyl, cycloalkyl and phenyl, RK is selected from lower alkyl, lower alkoxy and phenyl, each phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, lower alkylsulfonyl, phenylsulfonyl, phenyl and RExe2x80x94OCOxe2x80x94, and each cycloalkyl can be substituted by lower alkyl, hydroxy, oxo or RExe2x80x94OCOxe2x80x94;
3) R5 and R6, being the same or different, are selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl and pyridyl, the lower alkyl can be substituted by a group selected from hydroxy, lower alkoxy, cycloalkyl, cycloalkenyl, phenyl, naphthyl, pyridyl, thienyl, imidazolyl, phthalimido, piperidyl, piperazinyl, morpholinyl, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94, RHxe2x80x94N(RJ)COxe2x80x94, RKxe2x80x94CONHxe2x80x94 and xe2x80x94CONHOH, the piperidyl, piperazinyl or morpholinyl can be substituted by lower alkyl, phenyl or naphthyl, RE is selected from hydrogen, lower alkyl and phenyl, RF and RG, being the same or different, are selected from hydrogen, lower alkyl, cycloalkyl and phenyl, RH and RJ, being the same or different, are selected from hydrogen, lower alkyl, cycloalkyl and phenyl, RK is selected from lower alkyl, lower alkoxy and phenyl, each phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, lower alkylsulfonyl, phenylsulfonyl, phenyl and RExe2x80x94OCOxe2x80x94, and each cycloalkyl can be substituted by a group selected from lower alkyl, hydroxy, oxo and RExe2x80x94OCOxe2x80x94;
4) R5 and R6 join each other to form a nonaromatic heterocyclic ring selected from a morpholine ring, a piperidine ring, a piperazine ring, a pyrroline ring and a homopiperazine ring, the nonaromatic heterocyclic ring can be substituted by lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl or RAxe2x80x94COxe2x80x94, the lower alkyl can be substituted by hydroxy, phenyl, naphthyl, RBxe2x80x94Oxe2x80x94, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 or xe2x80x94CONHOH, RA is lower alkyl, halogeno-lower alkyl, lower alkoxy or phenyl, RB is lower alkyl or phenyl, RE is hydrogen, lower alkyl or phenyl, RF and RG, being the same or different, are hydrogen, lower alkyl, cycloalkyl or phenyl, each phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, lower alkylsulfonyl, phenylsulfonyl, phenyl and RExe2x80x94OCOxe2x80x94, and each cycloalkyl can be substituted by a group selected from lower alkyl, hydroxy, oxo and RExe2x80x94OCOxe2x80x94;
5) R7 is selected from hydrogen, lower alkyl, cycloalkyl, hydroxy, carboxy, mercapto, phenyl, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 and xe2x80x94CONHOH, the lower alkyl can be substituted by a group selected from cycloalkyl, hydroxy, carboxy, mercapto, phenyl, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 and xe2x80x94CONHOH, RB is lower alkyl or phenyl, RC is lower alkyl or phenyl, RD is lower alkyl or phenyl, RE is lower alkyl or phenyl, RF and RG, being the same or different, are hydrogen, lower alkyl, cycloalkyl or phenyl, each phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, lower alkylsulfonyl, phenylsulfonyl, phenyl and RExe2x80x94OCOxe2x80x94, and each cycloalkyl can be substituted by lower alkyl, hydroxy, oxo or RExe2x80x94OCOxe2x80x94;
6) R7 joins with sulfur adjacent to A1 to form a nonaromatic heterocyclic ring selected from a thiolactone ring and a dithiolane ring;
7) A1 is lower alkylene; and
8) A2 is lower alkylene.
More preferred examples of the present compound are the following.
Compounds and salts thereof wherein the group(s) in the general formula [I] is defined by anyone selected from the following 1) to 11) or any combinations consisting of 1) to 11).
1) R1 is selected from hydrogen, lower alkyl, phenyl, RAxe2x80x94COxe2x80x94, RCxe2x80x94Sxe2x80x94 and a group of the following formula [II], and the lower alkyl can be substituted by phenyl or lower alkoxycarbonyl, 
RA is selected from lower alkyl, lower alkoxy, phenyl, pyridyl, phenyl-lower alkoxy and RFxe2x80x94N(RG)xe2x80x94, RC is phenyl, RF is lower alkyl, and RG is hydrogen;
2) R2 is selected from hydrogen, lower alkyl, lower alkenyl and phenyl, the lower alkyl can be substituted by a group selected from lower alkoxy, cycloalkyl, cycloalkenyl, adamantyl, phenyl, naphthyl, pyridyl and RBxe2x80x94Oxe2x80x94, the phenyl can be substituted by a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, nitro and phenyl, the lower alkenyl can be substituted by phenyl, and RB is phenyl;
3) R3 is selected from hydrogen and lower alkyl, and the lower alkyl can be substituted by phenyl;
4) R4 is selected from hydrogen, lower alkyl and phenyl, the lower alkyl can be substituted by a group selected from hydroxy, cycloalkyl, phenyl, naphthyl, pyridyl, thienyl, imidazolyl, toluenesulfonylguanidino, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RFxe2x80x94N(RG)xe2x80x94 and RKxe2x80x94CONHxe2x80x94, each phenyl can be substituted by a group selected from hydroxy, lower alkoxy, halogen, nitro, lower alkanoylamino, phenylsulfonyl and phenyl, RC is selected from hydrogen, lower alkyl and phenyl, RD is selected from lower alkyl and phenyl, RF and RG are hydrogen, and RK is lower alkoxy. When R4 is lower alkyl, terminal carbon of the lower alkyl can join with carbon to which the alkyl is bonded to form a cycloalkyl ring;
5) R5 is selected from hydrogen and lower alkyl;
6) R6 is selected from lower alkyl and pyridyl, the lower alkyl can be substituted by a group selected from pyridyl, imidazolyl, phthalimido, piperidyl, piperazinyl, morpholinyl, RExe2x80x94OCOxe2x80x94, RFxe2x80x94N(RG)xe2x80x94, RHxe2x80x94N(RJ)COxe2x80x94 and RKxe2x80x94CONHxe2x80x94, RE is selected from hydrogen and lower alkyl, RF and RG, being the same or different, are selected from hydrogen, lower alkyl, cycloalkyl and phenyl, RH and RJ, being the same or different, are selected from hydrogen and lower alkyl, RK is lower alkoxy, and the piperazinyl can be substituted by lower alkyl;
7) R5 and R6 join each other to form a nonaromatic heterocyclic ring selected from a morpholine ring, a piperidine ring, a piperazine ring, a pyrroline ring and a homopiperazine ring, the piperazine ring or the homopiperazine ring can be substituted by lower alkyl, cycloalkyl, phenyl or RAxe2x80x94COxe2x80x94, the lower alkyl can be substituted by hydroxy, phenyl or RExe2x80x94OCOxe2x80x94, RA is lower alkyl, lower alkoxy or halogeno-lower alkyl, and RE is hydrogen or lower alkyl;
8) R7 is selected from hydrogen, lower alkyl, hydroxy, mercapto, phenyl, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RDxe2x80x94COSxe2x80x94, RExe2x80x94OCOxe2x80x94, xe2x80x94CONHOH and RFxe2x80x94N(RG)xe2x80x94, the lower alkyl can be substituted by a group selected from hydroxy, mercapto, phenyl, RBxe2x80x94Oxe2x80x94, RCxe2x80x94Sxe2x80x94, RD COSxe2x80x94, RExe2x80x94OCOxe2x80x94, xe2x80x94CONHOH and RFxe2x80x94N(RG), RB is phenyl, RC is phenyl, RD is lower alkyl or phenyl, RE is hydrogen or lower alkyl, and RF and RG are lower alkyl;
9) R7 joins with sulfur adjacent to A1 to form a nonaromatic heterocyclic ring selected from a thiolactone ring and a dithiolane ring;
10) A1 is lower alkylene; and
11) A2 is lower alkylene.
Further preferred examples of the present compound are the following.
Compounds and salts thereof wherein the group(s) in the general formula [I] is defined by anyone selected from the following 1) to 10) or any combinations consisting of 1) to 10).
1) R1 is selected from hydrogen, RAxe2x80x94COxe2x80x94 and a group of the following formula [II], 
RA is selected from lower alkyl, phenyl and pyridyl;
2) R2 is lower alkyl or phenyl, the lower alkyl can be substituted by a group selected from cycloalkyl, cycloalkenyl, adamantyl, phenyl and phenoxy, and the phenyl can be substituted by halogen;
3) R3 is hydrogen;
4) R4 is hydrogen or lower alkyl, the lower alkyl can be substituted by a group selected from phenyl, naphthyl, lower alkylthio and RDxe2x80x94COSxe2x80x94, RD is lower alkyl, and the phenyl can be substituted by a group selected from hydroxy, lower alkoxy, halogen, nitro and phenyl;
5) R5 is hydrogen;
6) R6 is lower alkyl, the lower alkyl can be substituted by a group selected from pyridyl, piperidyl, piperazinyl and RFxe2x80x94N(RG)xe2x80x94, RF and RG, being the same or different, are selected from hydrogen, lower alkyl and cycloalkyl, and the piperazinyl can be substituted by lower alkyl;
7) R5 and R6 join each other to form a nonaromatic heterocyclic ring selected from a piperidine ring, a morpholine ring and a piperazine ring, the piperazine ring can be substituted by lower alkyl;
8) R7 is hydrogen;
9) A1 is lower alkylene; and
10) A2 is lower alkylene.
The most preferred examples of the present compound are the following.
Compounds and salts thereof wherein the group(s) in the general formula [I] is defined by anyone selected from the following 1) to 10) or any combinations consisting of 1) to 10).
1) R1 is selected from acetyl, benzoyl and a group of the following formula [II]; 
2) R2 is selected from 2-cyclohexylethyl, 2-cyclopentylethyl, 2-(1-adamantyl)ethyl, 2-(cyclohexen-1-yl)ethyl, phenethyl and 3-(4-fluorophenyl)propyl;
3) R3 is hydrogen;
4) R4 is selected from methyl, acetylthiomethyl, benzyl, 2-naphthylmethyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-biphenylylmethyl, 4-nitrobenzyl, 3-nitro-4-biphenylylmethyl, 4-methoxybenzyl and 4-isopropoxybenzyl;
5) R5 is hydrogen;
6) R6 is selected from 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(diisopropylamino)ethyl, N-methyl-2-(cyclohexylamino)ethyl, 2-(2-pyridyl)ethyl, 2-(1-piperidyl)ethyl and 2-(4-methylpiperazinyl)ethyl;
7) R5 and R6 join each other to form a group selected from 1-piperidyl, 4-morpholinyl and 4-methyl-1-piperazinyl;
8) R7 is hydrogen;
9) A1 is ethylene;
10) A2 is methylene.
The most preferred practical examples of the present compound are the following compounds and salts thereof.
1) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(2-naphthyl)propionamide: 
2) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(N-methylcyclohexylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
3) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(diethylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
4) (2S)-2-[3-[2-(Benzoylthio)ethyl]-3-phenethylureido]-N-[2-(diethylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
5) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-(4-biphenylyl)-N-[2-(dimethylamino)ethyl]propionamide: 
6) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(diisopropylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
7) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(4-methoxyphenyl)propioamide: 
8) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
9) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(4-nitrophenyl)propionamide: 
10) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]propionamide: 
11) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-(4-nitrophenyl)-N-[2-(2pyridyl)ethyl]propionamide: 
12) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[3-(1-imidazolyl)propyl]-3-(4-nitrophenyl)propionamide: 
13) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)propionamide: 
14) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-(4-nitrophenyl)-N-[2-(piperidino)ethyl]propionamide: 
15) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(dimethylamino)ethyl]-3-(4-isopropoxyphenyl)propionamide: 
16) (2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-(4-nitrophenyl)propionamide: 
17) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-(2-cyclohexylethyl)ureido]propionyl]-4-methylpiperazine: 
18) 1-[(2S)-2-[3-[2-(Acethylthio)ethyl]-3-(2-cyclopenthylethyl)ureido]propionyl]-4-methylpiperazine: 
19) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-[2-(cyclohexen-1-yl)ethyl]ureido]propionyl]-4-methylpiperazine: 
20) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-[3-(4-fluorophenyl)propyl]ureido]propionyl]-4-methylpiperazine: 
21) 1-[(2R)-3-(Acetylthio)-2-[3-[2-(acetylthio)ethyl]-[3-[2-(acetylthio)ethyl]-3-phenethylureido]propionyl]-4-methylpiperazine: 
22) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-henethylureido]propionyl]morpholine: 
23) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-(2-cyclohexylethyl)ureido]propionyl]piperidine: 
24) 1,1xe2x80x2-Dimethyl-4,4xe2x80x2-[(2S,2xe2x80x2S)-2,2xe2x80x2-[3,3xe2x80x2-diphenethyl-3,3xe2x80x2-(2,2xe2x80x2-dithiodiethyl)diureido]-3,3xe2x80x2-diphenyldipropionyl]dipiperazine: 
25) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-[2-(1-adamantyl)ethyl]ureido]propionyl]-4-methylpiperazine: 
26) 1-[(2S)-2-[3-[2-(Acetylthio)ethyl]-3-[2-(1-adamantyl)ethyl]ureido]propionyl]morpholine: 
27) 1,1xe2x80x2-Dimethyl-4,4xe2x80x2-[2S,2xe2x80x2S)-2,2xe2x80x2-[3,3xe2x80x2-diphenethyl-3,3xe2x80x2-[2,2xe2x80x2-(dithio)diethyl]diureido]dipropionyl]dipiperazine: 
28) 1,1xe2x80x2-[(2S,2xe2x80x2S)-2,2xe2x80x2-[3,3xe2x80x2-Bis(2-cyclohexylethyl)-3,3xe2x80x2-[2,2xe2x80x2-(dithio)diethyl]diureido]dipropionyl]-4,4xe2x80x2-dimethyldipiperazine: 
29) 1,1xe2x80x2-[(2S,2xe2x80x2S)-2,2xe2x80x2-[3,3xe2x80x2-Bis[2-(1-adamantyl)ethyl]-3,3xe2x80x2-[2,2xe2x80x2-(dithio)diethyl]diureido]dipropionyl]-4,4xe2x80x2-dimethyldipiperazine: 
30)1,1xe2x80x2-[(2S,2xe2x80x2S)-2,2xe2x80x2-[3,3xe2x80x2-Bis(2-cyclopentylethyl)-3,3xe2x80x2-[2,2xe2x80x2-(dithio)diethyl]diureido]dipropionyl]-4,4xe2x80x2-dimethyldipiperazine: 
Since the present synthetic intermediate is selected corresponding to the chemical structure of the present compound, preferred examples of the present synthetic intermediate are also selected corresponding to the preferred examples of the present compound.
A typical synthesis route scheme of the present compound is shown below. 
The present compound [I] can be synthesized through various synthesis routes, for example, as shown in the above reaction route scheme. These synthesis methods are shown every route below. However, these routes exemplify typical routes and do not show all methods. Detailed synthesis methods are described in Examples later.
Route A) [IV]xe2x86x92[VII]xe2x86x92[III]xe2x86x92[I]
Route B) [IV]xe2x86x92[X]xe2x86x92[III]xe2x86x92[I]
Route C) [IV]xe2x86x92[VII]xe2x86x92[XI]xe2x86x92I]
Route D) [IV]xe2x86x92[XI]xe2x86x92[I]
Route E) [IV]xe2x86x92[X]xe2x86x92[I]
The synthesis methods of these routes are described in more detail below. 
[wherein Ra is hydrogen, lower alkyl phenyl or benzyl. The same definitions are applied hereinafter.]
The ester derivative [IV] is reacted with the amino alcohol derivative [V] in the presence of the condensation agent (for example, 1,1xe2x80x2-carbonyldiimidazole [VI]) and the base to convert it into the urea derivative [VII], and the resulting urea derivative is reacted with the amine derivative [VIII] to give the compound represented by the formula [III] (the present synthetic intermediate). Then, the obtained compound [III] is condensed with the thiol derivative [IX] by Mitsunobu reaction to give the present compound [I]. 
The ester derivative [IV] is reacted with the amine derivative [VIII] to convert it into the amide derivative [X], and the resulting amide derivative is reacted with the amino alcohol derivative [V] in the presence of the condensation agent (for example, 1,1xe2x80x2-carbonyldiimidazole [VI]) and the base to give the compound represented by the formula [III] (the present synthetic intermediate). Then, the present compound [I] is obtained in the same manner as by the route A). 
The urea derivative [VII] obtained according to the method of the route A) is condensed with the thiol derivative [IX] by Mitsunobu reaction to give the compound represented by the formula [XI]. Then, the obtained compound [XI] is condensed with the amine derivative [VIII] by the conventional method to give the present compound [I]. 
The ester derivative [IV] is reacted with the aminothiol derivative [XII] in the presence of the condensation agent (for example, 1,1xe2x80x2-carbonyldiimidazole [VI]) and the base to give the compound [XI]. Then, the obtained compound [XI] is condensed with the amine derivative [VIII] by the conventional method to give the present compound [I]. 
The amide derivative [X] obtained by the method of the route B) is reacted with the aminothiol derivative [XII] in the presence of the condensation agent (for example, 1,1xe2x80x2-carbonyldiimidazole [VI]) and the base to give the present compound [I].
In the above-mentioned synthesis methods, when the reactant has a hydroxy, thiol or amino group in its molecule, these groups can be protected with suitable protecting groups, if necessary, and these protecting groups can also be removed by the conventional method after reaction. When the reactant has a carboxyl group in its molecule, the carboxyl group can be esterified, if necessary, and the ester can also be converted into a carboxylic acid by hydrolysis or acidolysis.
In the present compound, when R7 joins with sulfur adjacent to A1 to form a thiolactone ring or a dithiolane ring, the present compound can also be synthesized by the following methods other than the above-mentioned routes.
When R7 is RExe2x80x94OCOxe2x80x94 and R1 is hydrogen in the formula [I], the thiolactone ring can also be synthesized by condensing these groups.
When R7 is mercapto and R1 is hydrogen in the formula [I], the dithiolane ring can be synthesized by joining these groups. Namely, the dithiolane ring is synthesized by forming intramolecular disulfide.
The compounds obtained by the above-mentioned methods can be converted into the above-mentioned salts by the conventional method.
The chemical structural feature of the present compounds is that the compounds have urea structure as basic structure and have a sulfur atom and an amide bond in side chains. Few studies of such drugs having the urea structure as basic skeleton have been reported. Moreover, no drug having a sulfur atom in a side chain has hitherto practically been reported. Limiting drugs to those having the TNF-xcex1 production inhibitory effects, which is an object of the present invention, no drug having a chemical structure similar to the present compound is known at all.
The present inventors precisely studied the synthesis of the compounds having the urea structure as basic structure which thus had been hitherto hardly studied, prepared the many novel compounds, found that these novel compounds have the excellent TNF-xcex1 production inhibitory effects, and completed the present invention. The present inventors found also the novel compounds which are useful as the synthetic intermediates of the present compounds in the process of the study of the synthesis of the present compounds. The present compounds exhibit the effects both in state where the sulfur atom in the side chain joins with various groups (represented by R1 in the formula [I] except for hydrogen) and in the state where the sulfur atom takes the form of SH (R1 in the formula [I] is hydrogen). When R1 is used as a protecting group of the SH group, the protecting group is sometimes removed by hydrolysis and the like and the resulting form of SH exhibits the effects. When the present compounds contain a carboxylate in their molecule, the present compounds exhibit the effects even in the ester state. The ester linkage is sometimes subject to hydrolysis and the like and the resulting form of a carboxylic acid exhibits the effects. When the present compounds contain a group which is converted into a free hydroxy or amino group, the present compounds can be administered in state where these groups are protected with suitable protecting groups. The present compounds can be administered in state where these protecting groups are removed.
The TNF-xcex1 production inhibitory effects of the present compounds were examined in order to study utility of the present compounds. Details will be described in the item of pharmacological test below. Studying in vitro or in vivo inhibitory effects on liberation of TNF-xcex1 caused by stimulation of lipopolysaccharide (LPS), the present compounds exhibited the excellent TNF-xcex1 production inhibitory effects.
TNF-xcex1 production is known to be closely related to crises of autoimmune diseases such as rheumatoid arthritis, Crohn""s disease and systemic lupus erythematosus, cachexia, acute infectious disease, allergy, pyrexia, anemia, diabetes and the like. Compounds which inhibit its production like the present compounds are expected to be useful for treatment of these various diseases.
The present compound can be administered orally or parnterally. Examples of dasage forms are tablets, capsules, granules, powders, injections and the like. The present compound can be formulated into preparations by the conventional methods. For example, oral preparations such as tablets, capsules, granules and powders can be produced by adding optionally diluents such as lactose, crystalline cellulose, starch and vegetable oil; lubricants such as magnesium stearate and talc; binders such as hydroxypropylcellulose and polyvinyl pyrrolidone; disintegrator such as calcium carboxymethylcellulose or low-substituted hydroxypropylmethylcellulose; coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or film forming agent such as gelatin film.
The dosage of the present compound can be selected suitably according to the symptom, age, dosage form and the like. In case of the oral preparation, the present compound can be administered once to several times per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000 mg.
Examples of preparations and formulations and results of pharmacological test of the present invention are shown below. These examples do not limit the scope of the invention, but are intended to make the invention more clearly understandable.
Preparation of Compounds